The burden of palmoplantar pustulosis: A Canadian population-based study of inpatient care, emergency departments, and outpatient clinics

Background Not much is known about the burden of palmoplantar pustulosis (PPP). Objectives To document the burden of PPP in Canada, and to compare with psoriasis vulgaris (PV). Methods Adult Canadians (excluding the province of Quebec) hospitalized or visiting an emergency department (ED) or hospital-/community-based clinic between April 1, 2007, and March 31, 2020, with a diagnostic code indicating PPP (ICD-10-CA: L40.3) or PV (ICD10-CA: L40.9 or L40.0) were identified using Canadian administrative data. 10-year prevalent- and 3-year incident-based approaches were conducted. Costs were determined when the most responsible diagnosis (MRD) for the admission was PPP or PV (MRD costs) and for all reasons (all-cause costs). Results In the prevalence analysis, the 10-year mean (standard deviation [SD]) and MRD costs were $544 ($1874) for PPP and $222 ($1828) for PV (P < .01). In the incidence analysis, PPP patients had higher 3-year mean (SD) MRD costs ($1078 [$2705]) than PV ($503 [$2267]) (P < .01). All-cause costs were lower for the PPP cohort in the prevalent and incident analyses. There were no differences in all-cause inpatient mortality between PPP and PV. Limitations Physician and prescription data were not available. Conclusion PPP patients incurred significantly higher MRD costs than PV patients.


INTRODUCTION
Palmoplantar pustulosis (PPP), a rare subtype of pustular psoriasis, has been defined as having ''primary, persistent ([3 months), sterile, macroscopically visible pustules on palms and/or soles''. 1 Since PPP is a rare disease, the epidemiology and burden associated with it is not well understood. A recent structured review 2 identified 4 studies reporting on the prevalence of PPP which ranged from 0.05% (Sweden) 3 to 0.12% (Japan). 4 To our knowledge, only 1 study, 5 which was not included in the review by Kharawala et al 2 , attempted to capture the economic costs associated with PPP, which were found to be similar to a matched cohort of patients with psoriasis vulgaris (PV).
A recent population-based study of emergency department (ED) and inpatient care from the province of Ontario in Canada (13.6 million habitants) identified 115 ED visits and 17 hospitalizations with PPP over a 10-year period. 6 However, this study did not provide any details on patient characteristics or on the ED visit and hospital admission (eg, length of stay and costs). To fill an important gap in the literature, the study objectives were to document the burden of PPP and to compare with PV patients.

Study overview and data sources
Canadian adults hospitalized and seen in an ED or hospital-/community-based outpatient clinic for either PPP (PPP cohort) or PV (PV cohort) were identified using de-identified patient-level data from 2 databases from the Canadian Institute for Health Information (CIHI) 7 : the Discharge Abstract Database (DAD) and the National Ambulatory Care Reporting System (NACRS). DAD 8 captures administrative, demographic, and clinical information on all hospital discharges in Canada. Although NACRS coverage varies across the study years, NACRS 9 captured approximately 65% (2016-17) to 85% (2019-20) 10 of all hospital-/community-based ED and ambulatory care visits in Canada. All-cause inpatient or ED mortality (''inpatient mortality'') in the facility is available in DAD or NACRS while deaths available in the community are not. Data from the province of Quebec (approximately 23% of the Canadian population) were not included in this study.
Up to 20 possible International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada (ICD-10-CA) diagnostic codes are recorded for each encounter captured in DAD and NACRS. Each diagnostic code is categorized as either a 'most responsible diagnosis (MRD)' (ie, the diagnosis determined to have been responsible for the greatest portion of the patient's length of stay) or as another diagnosis/comorbidity. In addition, costs associated with each encounter in DAD and NACRS are available based on CIHI costing methodology. 11 CIHI Meaningless but Unique Patient Identifier, which is common to DAD and NACRS, was used to link the 2 databases.

Study population
Canadian adults ($18 years of age) hospitalized or visiting an ED or hospital-/community-based outpatient clinic between April 1, 2017, to March 31, 2020, with a diagnostic code indicating PPP or PV were included in the study. The PPP and PV cohorts were defined by ICD-10-CA codes of L40.3 and L40.0 or L40.9, respectively. Individuals with diagnostic codes of acrodermatitis continua (ICD-10-CA code: L40.2) or dermatitis due to substances taken internally (ICD-10-CA code: L27 category, which includes generalized or local skin eruption due to drugs and medicaments taken internally) were excluded. A prevalent and an incident approach were used.

Prevalence analysis
The number of unique patients with at least 1 DAD or NACRS record with a diagnostic code indicating PPP for the PPP cohort and PV for the PV cohort were used to estimate the number of prevalent cases over the 10-year period (April 1, 2010, to March 31, 2020). The study population was described in terms of age, sex, medical history, and several comorbidities. DAD and NACRS data were used to estimate 10-year healthcare resource utilization, costs, and all-cause inpatient mortality associated with our prevalent cohorts.

Incidence analysis
Unique patients with a PPP or PV diagnostic code over a 5-year time period (April 1, 2012, to March 31, 2017) without any PPP (PPP incident cohort) or PV (PV incident cohort) diagnostic code in the 5 previous years (April 1,2007, to March 31, 2012) defined our incident cases. Incident cases of PPP and PV were identified as the first DAD or NACRS record with an MRD of PPP and PV, respectively. Restricting our incident cases to those with an MRD of PPP CAPSULE SUMMARY d Palmoplantar pustulosis (PPP) patients hospitalized or visiting an emergency department (ED) or a hospital-/ community-based clinic due to a most responsible diagnosis (MRD) of PPP incur higher costs than patients with a MRD of psoriasis vulgaris. (PPP cohort) or PV (PV cohort) was to ensure that the index event (eg, hospitalization or visit to ED or outpatient clinic) was directly attributable to PPP or PV and not to an unrelated condition. All of our 5-year incident cases had a minimum of 3-years of follow-up (up to March 31, 2020). CIHI data were used to document patient characteristics at time of index, 3year healthcare resource utilization, costs, and allcause inpatient mortality following the index event.

Statistical analysis
Prevalence and incidence rates were calculated by dividing the number of prevalent/incident cases identified by the Canadian population estimates (except Quebec) during the same time period. The baseline characteristics of the PPP and PV populations were compared using student T-tests and chisquare tests. Several analyses were conducted to address some of the limitations associated with the coverage of ED and outpatient clinics captured in NACRS, which may result in an underestimate of the prevalence or incidence numbers. The first sensitivity analysis used data from Ontario only (38% of the Canadian population) as 100% of all ED visits in Ontario are reported in NACRS. The second sensitivity analysis used data from Alberta data only (12% of the Canadian population) as 100% of all ED visits and 100% of all hospital-/community-based outpatient clinics are captured in NACRS in Alberta.
The economic burden of PPP and PV was estimated using 2 approaches. DAD and NACRS records for which the MRD was PPP or PV (ie, MRD costs) were first used to identify healthcare resource utilization and costs directly attributable to PPP or PV. Our second costing approach included all health care resources consumed by the study populations independently of the presence of a PPP/PV diagnostic code (ie, all-cause costs).
Multivariable generalized linear models (GLM) (log link with negative binomial distribution for count data and gamma distribution for costs) adjusting for baseline characteristics (age, sex, and comorbidities) were used to compare the number of admissions, length of stay, and costs between the PPP and PV cohorts. Multivariable logistic regressions adjusting for baseline characteristics were used to compare all-cause inpatient mortality between PPP and PV. Cells for which between 1 and 4 individuals contributed to the data were not disclosed as this is a requirement when using CIHI data. All costs were expressed in Canadian dollars unless otherwise stated.

Prevalence analyses
Our 10-year analysis (April 1, 2010, to March 31, 2020) identified 338 and 24,828 unique individuals with a PPP and PV record, respectively, yielding prevalence rates of 1.54 per million individuals for PPP and 113.13 per million individuals for PV. Our sensitivity analyses indicated that prevalence rates were higher in Ontario where ED visit reporting is mandatory (PPP: 1.71 per million; PV: 114.69 per million) and in Alberta where both ED visit and hospital-/community-based clinic visit reporting is mandatory (PPP: 3.45 per million; PV: 272.85 per million).

DISCUSSION
The results of these analyses using Canadian data on hospitalization and visits to the ED and outpatient clinics makes several contributions to the emerging literature on PPP. Due to a mandatory reporting of ED and hospital-/community-based clinics in Alberta compared to the other Canadian provinces/territories, the prevalence and incidence rates of PPP were the highest in Alberta at 3.45 per million individuals and 1.78 per million individuals, respectively. One of the key findings of this study is that the PPP MRD costs were higher than PV MRD costs by a factor ranging from 2.1 (incidence analysis) to 2.4 (prevalence analysis). However, the PPP cohort had lower costs than the PV cohort when all-cause admissions were considered in both ND, Non disclosable due to cell count less than 5; PPP, palmoplantar pustulosis; PV, psoriasis vulgaris; SD, standard deviation.
the incident and prevalent approaches. These results highlight the need to document the economic burden directly attributed to the condition under study (eg, MRD cost) versus the burden associated with complications or comorbidities associated with PPP and PV. Our results showed that only a small  part of the healthcare resource use and associated costs were attributable to an MRD of PPP or PV when compared to all-cause admissions. Another important finding of our study is that we did not find any difference in all-cause inpatient mortality between PPP and PV in our prevalent and incident analyses. Finally, in addition to our prevalent analysis, we undertook an incident analysis in which PPP patients were followed for 3 years after the index event defined by an MRD of PPP. To our knowledge, no other studies have taken an incidence approach when studying PPP. Compared to an Ontario-specific study in Canada which identified 132 hospital and ED records with a PPP diagnostic code over a 10-year period, 6 our results for Ontario (data not shown) are similar. However, we also included all other Canadian provinces/territories excluding Quebec, while providing additional insights on patient characteristics and the burden of PPP in Canada. It is difficult to compare our study findings with the limited international literature on PPP due to differences in study design, data availability, or health care settings. Since we only had access to hospitalizations and visits to the ED and outpatient clinics, our prevalence numbers are lower than those reported in other studies in which authors had also access to physician and pharmacy data. 2 It is also difficult to compare our cost figures with the U.S. study which also included physician and pharmacy costs. 5 Since the U.S. study did not provide the cost figures for the inpatient and ED use, we were not able to compare our hospitalization/ED cost results.
Several limitations associated with our study should be noted when interpreting the results. First, similar to other studies relying on administrative data, there is a possibility of miscoding or underreporting the conditions under study. For example, while it was assumed that healthcare resource use with a diagnostic code of PPP will be those from genuine PPP patients, some PPP patients may have not received a PPP diagnostic code. A second limitation is related to the data capture of the ED and hospital-/community-based outpatient clinic data. As opposed to hospitalizations, reporting of ED visits is only mandatory in a few Canadian provinces while reporting of hospital-and community-based outpatient clinic visits is only mandatory in Alberta. To address this issue, we reported prevalence and incidence rates for Ontario (mandatory reporting of ED visits) and Alberta (mandatory reporting of ED and outpatient clinic visits). Third, we did not have any information on physician and pharmacy data or mortality in the community. As a result, this study underestimates the true impact of PPP in Canada. Finally, since administrative data were used, we did not have access to quality-of-life data to document the burden of PPP on health-related quality of life. We also did not have any information on work/ school productivity losses or out of pocket expenditures incurred by PPP patients and their caregivers. This is left for future research.

CONCLUSIONS
Our study results indicate that PPP patients incurred significantly higher costs than PV patients when healthcare resource utilization was due to an MRD of PPP or PV but not when all cause health care resource use was considered. We also did not find any difference in all-cause inpatient mortality between PPP and PV.